Wednesday, January 15, 2025 1/15/2025

Role of laterodorsal tegmental nucleus cholinergic and glutamatergic inputs to the ventral tegmental area in drug reward and sensitization

Award Number: R15DA041694
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): The contributions of midbrain dopamine (DA) systems to drug reward and to drug sensitization are clear. It is not clear which brain circuits most importantly contribute to changes in DA neurons following drug exposure. The laterodorsal tegmental nucleus (LDTg) provides parallel cholinergic (ACh) and glutamatergic (GLU) inputs to ventral tegmental area (VTA) DA neurons that importantly control the activity of midbrain DA systems. In rats and mice ACh and GLU inputs to the VTA modulate the rewarding effects of cocaine and of opiates. Understanding the contributions of LDTg ACh or GLU inputs to the VTA to drug reward and addiction requires a means of selectively targeting these inputs. Preliminary results in Cre transgenic mice indicate that selective optogenetic excitation (via channelrhodopsin 2) of LDTg ACh but not GLU axons in the VTA is rewarding. Selective optogenetic inhibition of LDTg GLU cells (via halorhodopsin) reduces the induction of cocaine locomotor sensitization (an established model that quantifies behavioral adaptations induced by repeated drug exposure thought to reflect underlying neural changes important for drug addiction) but does not affect the acquisition of cocaine conditioned place preference (CPP - an established model that tests primary drug reward). This suggests that these LDTg GLU afferents to the VTA may be a site at which GLU plasticity is important for addictive behaviors to occur. Considering the above, this project will test the hypothesis that LDTg ACh afferents to the VTA are important for reinforcement and for drug reward, and that LDTg GLU afferents to the VTA are important for the induction of sensitization following repeated drug exposure. Aim 1 focuses on establishing that excitation of LDTg ACh but not GLU axons to the VTA is rewarding. Aim 2 focuses on determining the contributions of LDTg ACh afferents to the VTA to cocaine (typical stimulant drug) and to morphine (typical opiate drug) CPP, by optogenetically inhibiting LDTg ACh or GLU axons in the VTA during drug conditioning. Aim 3 focuses on establishing the importance of LDTg GLU inputs to the VTA in the induction of drug sensitization by inhibiting LDTg GLU axons in the VTA during repeated cocaine- or morphine-induced locomotion testing. The critical contribution of the proposed research will be to define, for the first time, the sourc of VTA glutamate and acetylcholine that are important for drug reward and for sensitization. Characterizing the role of select LDTg inputs to the VTA in drug reward and locomotor sensitization will inform future studies aimed at developing mechanistically based interventions, targeting a specific neural circuit, seeking to prevent the long-lasting adaptations in DA neuron function that underlie addictive behaviors. In line with the goals of the R15 funding mechanism these experiments will continue to expose several Loyola University Chicago (a primary educational institution) undergraduate students to research in Behavioral Neuroscience.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2016	LOYOLA UNIVERSITY OF CHICAGO	1032 W SHERIDAN RD	CHICAGO	IL	60660	COOK	USA	Drug Use and Addiction Research Programs	000	1	11/22/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2016	LOYOLA UNIVERSITY OF CHICAGO	1032 W SHERIDAN RD	CHICAGO	IL	60660	COOK	USA	Drug Use and Addiction Research Programs	000	1	3/8/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	LOYOLA UNIVERSITY OF CHICAGO	1032 W SHERIDAN RD	CHICAGO	IL	60660	COOK	USA	Drug Use and Addiction Research Programs	000	1	3/26/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $415,167 )
2016	2016	LOYOLA UNIVERSITY OF CHICAGO	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Drug Use and Addiction Research Programs	001	1	4/20/2016	NEW	-$21,427
2016	2016	LOYOLA UNIVERSITY OF CHICAGO	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Drug Use and Addiction Research Programs	000	1	3/28/2016	NEW	$436,594
														Subtotal = $415,167

Grand Total All Awards = $415,167

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Role of laterodorsal tegmental nucleus cholinergic and glutamatergic inputs to the ventral tegmental area in drug reward and sensitization

Award Number: R15DA041694

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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